Summary:

Malaria is one of the major public health challenges in the world, causing more than one million deaths each year. The disease primarily affects children of the developing world. The available measures, such as personal protection or drugs, have proven insufficient to control the disease. A safe, affordable and efficacious paediatric malaria vaccine, which fits in the existing WHO Expanded Programme on Immunisation, would alleviate tremendous suffering in human kind.

Taking up this challenge, the PRIBOMAL consortium proposes to generate and test in preclinical models the safety and efficacy of an innovative malaria vaccine. The vaccine consists of a prime, to be administered at birth, of a novel recombinant BCG vector carrying preferentially multiple antigens derived from the Plasmodium falciparum parasite, the cause of malaria. The priming vaccine is followed at week 14 after birth by a booster vaccination using industrially developed, recombinant adenoviral vector carrying the identical Plasmodium falciparum antigens as the rBCG-based malaria vaccine.

Generation of these novel vaccine candidates as well as testing in established and novel pre-clinical models to determine potency and safety requires a combined European effort to bring together the required expertise on basic parasite biology, malaria epidemiology, disease onset and progression, recombinant vector technology, fundamental immunology, advanced animal models, and sophisticated proteomics. The international PRIBOMAL consortium bundles all required experience and as such is well positioned to successfully conduct this research programme.

Background:

It is estimated that more than 300 million individuals suffer from acute disease caused by the malaria parasite and that more than 1 million people succumb to this disease each year. Malaria, which is highly endemic in sub-Saharan Africa, claims its victims predominantly among children with the peak incidence of clinical malaria and 90% of malaria deaths in children younger than 5 years.

The challenge faced by the PRIBOMAL consortium is to design a safe, affordable paediatric malaria vaccine that provides long lasting protection against malaria and that fits within the existing WHO Expanded Programme on Immunisation (EPI) as to not further complicate operational vaccination logistics. The first vaccination that children would receive is at birth with Bacille Calmette-Guérin (BCG) a live and attenuated strain of Mycobacterium bovis, which is currently the only available vaccine against tuberculosis. BCG has been globally used as the TB vaccine for decades and has proven to be safe in hundreds of millions of children. In recent years BCG receives additional attention as a potential vaccine vehicle.

The PRIBOMAL consortium considers that a booster immunisation will be required to achieve long-lasting protection. Therefore, a choice was made to boost the rBCG.malaria vaccine, given at birth either alone or in addition to classical BCG, with a recombinant adenoviral vector, carrying the identical P. falciparum derived antigens, at 14 weeks after birth, thus compliant with WHO EPI schedule. Like rBCG, replication deficient adenoviral vector has an excellent safety record with tens of thousands of patients receiving recombinant adenoviral vectors in diverse gene therapy and vaccination trials without adverse effects.

To ultimately eradicate malaria disease hundreds of millions of vaccine dosages will need to be manufactured at low cost per dose, given that countries in sub-Saharan Africa do not have the economic means to purchase expensive vaccines. The manufacture of rBCG follows the exact same protocols and procedures as established for BGC and guarantees that sufficient doses of rBCG malaria vaccine can be manufactured at a price per dose similar to BCG. Consortium member Crucell has extensive expertise in adenoviral vaccine manufacturing, employing a mammalian cell line, coded PER.C6
, which can be cultured in suspension in large volumes Therefore, the PRIMOBAL consortium members consider the proposed two-component paediatric malaria vaccine to be affordable, thus applicable in developing countries such as sub-Saharan Africa.

Aim:

To demonstrate feasibility (safety and efficacy) in preclinical studies of a novel, affordable, two-component, paediatric malaria vaccine.

Expected results:

The ultimate deliverable of this programme is an efficacious paediatric malaria vaccine candidate that will eventually be advanced to GMP development and clinical trials. Besides reaching this aim, the consortium expects that during the execution of this programme extensive knowledge will be gathered regarding immunological features of different vaccination schedules, in combination with information on their protective ability. This information will help elucidate correlates of protection and facilitate rational design of future malaria vaccines.

Potential applications:

It can be envisioned that vaccines against other disease such as for instance HIV, TB or even cancer vaccine development can directly benefit from the PRIBOMAL research. Like malaria these diseases are considered to require vaccines that elicit strong humoral and cellular immune responses against a broad range of epitopes.

Coordinator:

Partners:

Nº	Principal Scientific Participants	Official Address	Other Information
2	Stefan Kaufmann	Max Planck Institute for Infection Biology Department of Immunology Schumannstrasse 21/22 D-10117 Berlin Germany	Tel: + 49/30-28460-500/-506 Fax: + 49/30-28460-501 E-mail: kaufmann@mpiib-berlin.mpg.de Website: www.mpiib-berlin.mpg.de
3	Marita Troye-Blomberg	Stockholm University Department of Immunology Wenner-Gren Institute Svante Arrheniusväg 16 S-106 91 Stockholm Sweden	Tel: + 46 (0) 8164164 Fax: + 46 (0) 8157356 E-mail: marita@imun.su.se Website: www.wgi.su.se
4	Tom Van der Poll	Academic Medical Centre University of Amsterdam Laboratory of Experimental Internal Medicine Meibergdreef 9 Postbus 22660 1100 DD Amsterdam The Netherlands	Tel: +31 (0) 20 5665910 Fax: +31 (0) 20 6977192 E-mail: t.vanderpoll@amc.uva.nl Website: www.amc.uva.nl
5	Robert Sauerwein	Radboud University Nijmegen Medical Centre Nijmegen Centre for Molecular Life Sciences 1.51 P.O.Box 9101 6500 HB Nijmegen The Netherlands	Tel: +31-24-3613663 Fax: +31-24-3541222 E-mail: r.sauerwein@mmbumcn.nl Website: www.malariavaccin.nl
6	Henriette Skovgaard Andersen	ACE BioSciences A/S Unsbjergvej 2a 5220 Odense SØ Denmark	Tel: +45 6565 2121 Fax: +45 6565 2122 E-mail: schrotz@acebiosciences.com Website:www.acebiosciences.com
7	Clemens Kocken	Biomedical Primate Research Centre Lange Kleiweg 139 Postbus 3306 2280 GH Rijswijk The Netherlands	Tel: +31 15 284 2699 Fax: +31 15 284 3999 Email: Thomas@bprc.nl Website: www.bprc.nl